Primary cortisol resistance is characterized by hypercortisolism and the absence of Cushingoid features. Clinical features, when present, are due to overproduction of nonglucocorticoid adrenal steroids, and both functional and quantitative abnormalities of the glucocorticoid receptor (GR) have been identified. The entire clinical spectrum may not yet be described, and the structural change(s) of the GR remains unknown. The principal investigator (PI) has recently identified a kindred with primary cortisol resistance and functionally abnormal GR. The index case was 6 7/12 y/o boy with iosexual precocious pseudopuberty caused by increased circulating adrenal androgens. The GR of intact mononuclear leukocytes from this individual have a decreased affinity for dexamethasone. The mother of the index case is affected, and 7 other first degree relatives are available for study. Only 5 other kindreds with primary cortisol resistance have been reported in the literature. To our knowledge, this is the first such kindred to be reported in the United States and the first demonstration of primary cortisol resistance causing iosexual precocity. The PI now has the unusual opportunity to determine the molecular abnormality that causes this disorder. The PI proposes to test the hypothesis that primary cortisol resistance in the kindred under study is due to an inherited functional abnormality of the CR that is caused by a mutation involving the glucocorticoid binding domain of the GR. To test the hypothesis the clinical characteristics, affinity of the GR for dexamethasone, and the sequence of the GR cDNA will be determined in each member of the kindred. If the three end points (clinical expression of primary cortisol resistance, functional abnormality of the GR, and primary structural abnormality of the glucocorticoid binding domain of the GR) segregate together in the kindred, this will constitute strong evidence in support of the major hypothesis. An understanding of this rare experiment of nature will provide greater insight into the mechanism of steroid hormone action and the clinical effects of GR abnormalities.